The H4R is the most recently identified and characterized histamine receptor (for reviews, see de Esch J. P., et al., Trends Pharmacol. Sci. 2005, 26(9), 462-469). The receptor is found in the bone marrow and spleen and is expressed on eosinophils, basophils, mast cells (Liu, C., et al., Mol. Pharmacol. 2001, 59(3), 420-426; dendritic cells, and human synovial cells from rheumatoid arthritis patients (Ikawa, Y., et al., Biol. Pham. Bull. 2005, 28(10), 2016-2018). More recently new variants of H4 receptors were described by Richard M. van Rijn, et al. (Biochem. J. (2008) Immediate Publication, doi:10.1042/BJ20071583).
In contrast to the other histamine receptors, H4R has a distinct expression profile on immune and other cells and modulates their function (immuno-modulatory role). Such cells include: mast cells, eosinophils, dendritic cells, T cells, monocytes and macrophages and antigen presenting cells in general. It is also present in endothelial and epithelial cells. The H4R appears to play a role in multiple functions of these cells, such as, activation, migration, differentiation, and cytokine and chemokine production. While the H4R has been identified and characterized, its functions and involvement in disease is still under study.
Currently, treatment of histamine related diseases generally focuses on the design of antagonists for H1R and H2R for the treatment of such diseases. For example, for allergies, antagonists of H1R such as loratadine, fexofenadine, diphenyl-hydramine, cetirizine, brompheniramine, cyproheptadine, dexchlorpheniramine, hydroxizine, ketotifen, mequitazine, oxotomide, mizolastine, ebastine, astemizole, carbinoxamide, alimemazine, buclizine, cyclizine hydrochloride, and doxylamine and others were developed. For stomach conditions exacerbated by gastric acid, antagonists of H2R such as cimetidine, ranitidine, famotidine, and nizatidine and others, were developed.
H4R antagonists have been proposed to have therapeutic potential in a number of inflammatory diseases including Inflammatory Bowel Disease (IBD), Systemic Lupus Erythematosus (SLE), atherosclerosis, allergy and asthma and others. (Zhang M, Thurmond R L, Dunford P J, The histamine H(4) receptor: a novel modulator of inflammatory and immune disorders. Pharmacol Ther. 2007 March; 113(3):594-606).
There are very few examples of compounds, much less of marketed therapeutics, that have H1R, H2R or H3R agonist activity. An example of a compound that has some H1R agonist activity is betahistine, N-methyl-2-pyridin-2-ylethanamine(betahistine), a H3 antagonist low H1 agonist. Betahistine is not a full H1 agonist. It is a potent H3 antagonist with a low H1 agonist activity. Betahistine has a very strong affinity for histamine H3 receptors and a weak affinity for histamine H1 receptors. Betahistine seems to dilate the blood vessels within the middle ear which can relieve pressure from excess fluid and act on the smooth muscle. It is used for the treatment of Menière syndrome (Review Article. CNS Drugs 2001: 15(11) 855-870). Examples of H3 agonists include: immepip 4-(3H-imidazol-4-ylmethyl)piperidine, imetit S-[2-(4-imidazolyl)ethyl]isothiourea. Immepip and Immetit, although not marketed drugs, are H3 receptor agonists and are currently used in studies in animals with aim to elucidate the H3 receptor function and derive possible therapeutic utility for brain disorders. Examples of H2 agonists include: Betazole 2-(2H-Pyrazol-3-yl)ethanamine, impromidine, N-[3-(imidazol-4-yl)-propyl]-N′-{2-[(5-methylimidazol-4-yl)methylthio]ethyl}-guanidine. Betazole and impromidine are histamine H2 agonists, used clinically as diagnostic tools to test gastric secretory function.
All examples of therapeutic molecules presented above do not utilize the H-receptor agonist activity as the major therapeutic function. In the case of Betahistine, the main therapeutic activity may not be predominantly due to the H1 agonist activity, but due to the H3 antagonist activity. The remainder agonist cases have a diagnostic utility or basic research and investigative use.
There is currently no commercially available drug to treat H4R modulated diseases that is a H4R agonist. Thus, there is an unmet and unperceived need to develop H4R agonists to treat H4R modulated diseases.
Anticholinergics
Anticholinergics are used in the treatment of COPD because they widen the airways by relaxing smooth muscle. They do this by blocking acetylcholine receptors. Acetylcholine is a chemical produced by the brain that causes muscle contraction, which in turn constricts airways. Anticholinergics are considered first-line therapy for COPD.
Examples of anticholinergics include, but are not limited to: tiotropium bromide (Spiriva®) and ipratropium bromide (Atrovent®). Atrovent is the only inhaled anticholinergic agent available in the United States.
Combination Inhalers
Recently, a new product called Advair® was FDA approved for asthma but it may also be beneficial in the treatment of COPD. It combines two medications that have been on the market, salmeterol (a longer acting beta2-agonist) and fluticasone (a steroid). Many patients require both medications to help prevent asthma or COPD symptoms from worsening, but until now were only available as separate inhalers. Advair® cannot be used to quickly relieve asthma or COPD symptoms, it is to be taken on a scheduled basis without regard for the symptoms the patient is having at that particular moment.
Another combination inhaler is Combivent®. It contains two medications: albuterol and ipratropium. Albuterol is an inhaled beta-agonist that works in the lungs to open airways and allow for easier breathing. It does this by stimulating the beta-receptors, which are a certain type of receptor located in the lungs, which help regulate constriction and dilation of the airways. Ipratropium is an anticholinergic used in the treatment of COPD to widen the airways by relaxing and opening air passages to the lungs, making it easier to breathe.
Corticosteroids
Corticosteroids are used to treat many health conditions. This drug class is mainly used for treating asthma, but it has been used for treating COPD. Oral corticosteroids decrease inflammation in the lungs that is associated with COPD. They may take longer to work than inhaled corticosteroids, since they have to travel through the bloodstream before they get to the lungs to work. Corticosteroids are only used in COPD patients who do not respond well to other standard therapies.
Inhaled Beta-2 Agonists
Beta2-agonists work in a manner similar to adrenaline, opening airways and easing breathing. They work by binding with, and thus stimulating, “beta2-receptors” that line the cell walls of the lungs and the bronchioles. The effect of this stimulation is to relax smooth muscles and widen the airways. In COPD, beta2-agonists should be scheduled instead of taken on as needed basis. Possible side effects to the beta2-agonists include shakiness, rapid heartbeat, and upset stomach.
Until recently, all available beta2-agonists were ones that worked quickly but lasted for a relatively short time—about 4-6 hours. Longer-acting beta2-agonists have since been introduced. They cannot be used to quickly relieve symptoms, because there is a delay before they start working. Currently there are two on the market: salmeterol (Serevent®) and formoterol (Foradil®). Longer-acting beta2-agonists are prescribed as maintenance medications which are to be taken on a scheduled basis without regard for the symptoms the patient is having at that particular moment. A short-acting beta2-agonist is best to treat acute symptoms of shortness of breath.
Inhaled Corticosteroids
Corticosteroids suppress the body's production of substances that trigger inflammation and reduce the production of substances that maintain inflammation. This drug class is mainly used for treating asthma, but it has been used for treating COPD. Corticosteroids are only used in COPD patients who do not respond well to other standard therapies.
Mucolytics
This class of drugs is used to thin the mucus associated with cough caused by thick mucus. Mucolytics make it easier to clear the mucus, which can be irritating and cause a cough.
Oral Beta-2 Agonists
Oral beta2-agonists works in a similar fashion to inhaled beta2-agonists, but they may take longer to work than the inhaled formulation. Oral beta-agonists must be absorbed in the digestive tract and travel through the circulatory system before they begin working in the lungs, whereas the inhaled formulations go straight to the lungs.
Theophyllines
Theophyllines appear to widen airways by relaxing the smooth muscles surrounding the airways. Theophylline is also used as a long-acting bronchodilator to prevent COPD symptoms. Taken orally as tablets, capsules, or liquids, theophylline is available in immediate-release and controlled-release formulations as well as injection (aminophylline).
Tritoqualine
7-Amino-4,5,6-triethoxy-3-(5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo[4,5-g]isoquinolin-5-yl) phthalide or Tritoqualine (TRQ) is a drug, currently formulated in 100 mg tablets and sold in pharmacies in Europe for the treatment of allergy.
Tritoqualine is an inhibitor of the enzyme histidine decarboxylase (HDC), which catalyzes histidine decarboxylation in vivo to produce histamine, an endogenous biogenic amine, plus carbon dioxide. Inhibiting histamine production in the body is proposed to ameliorate symptoms of allergy.
Leukotriene Receptor Antagonists
Leukotriene Receptor Antagonists (LRAs), e.g., Montelukast® and Zafirlukast®) have been traditionally used for the treatment of asthma.